1  2786 89 EZH2 RESTRICTS THE SMOOTH MUSCLE LINEAGE DURING MOUSE LUNG MESOTHELIAL DEVELOPMENT. DURING DEVELOPMENT, THE LUNG MESODERM GENERATES A VARIETY OF CELL LINEAGES, INCLUDING AIRWAY AND VASCULAR SMOOTH MUSCLE. EPIGENETIC CHANGES IN ADULT LUNG MESODERMAL LINEAGES ARE THOUGHT TO CONTRIBUTE TOWARDS DISEASES SUCH AS IDIOPATHIC PULMONARY FIBROSIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ALTHOUGH THE FACTORS THAT REGULATE EARLY LUNG MESODERM DEVELOPMENT ARE UNKNOWN. WE SHOW IN MOUSE THAT THE PRC2 COMPONENT EZH2 IS REQUIRED TO RESTRICT SMOOTH MUSCLE DIFFERENTIATION IN THE DEVELOPING LUNG MESOTHELIUM. MESODERMAL LOSS OF EZH2 LEADS TO THE FORMATION OF ECTOPIC SMOOTH MUSCLE IN THE SUBMESOTHELIAL REGION OF THE DEVELOPING LUNG MESODERM. LOSS OF EZH2 SPECIFICALLY IN THE DEVELOPING MESOTHELIUM REVEALS A MESOTHELIAL CELL-AUTONOMOUS ROLE FOR EZH2 IN REPRESSION OF THE SMOOTH MUSCLE DIFFERENTIATION PROGRAM. LOSS OF EZH2 DEREPRESSES EXPRESSION OF MYOCARDIN AND TBX18, WHICH ARE IMPORTANT REGULATORS OF SMOOTH MUSCLE DIFFERENTIATION FROM THE MESOTHELIUM AND RELATED CELL LINEAGES. TOGETHER, THESE FINDINGS UNCOVER AN EZH2-DEPENDENT MECHANISM TO RESTRICT THE SMOOTH MUSCLE GENE EXPRESSION PROGRAM IN THE DEVELOPING MESOTHELIUM AND ALLOW APPROPRIATE CELL FATE DECISIONS TO OCCUR IN THIS MULTIPOTENT MESODERM LINEAGE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  2072 29 EPIGENETIC CONVERSION OF HUMAN ADULT BONE MESODERMAL STROMAL CELLS INTO NEUROECTODERMAL CELL TYPES FOR REPLACEMENT THERAPY OF NEURODEGENERATIVE DISORDERS. TISSUE-SPECIFIC STEM CELLS, SUCH AS BONE MARROW-DERIVED MESODERMAL STROMAL CELLS (MSCS), ARE THOUGHT TO BE LINEAGE RESTRICTED AND, THEREFORE, COULD ONLY BE DIFFERENTIATED INTO CELL TYPES OF THE TISSUE OF ORIGIN. SEVERAL RECENT STUDIES, HOWEVER, SUGGEST THAT THESE TYPES OF STEM CELLS MIGHT BE ABLE TO BREAK BARRIERS OF GERM LAYER COMMITMENT AND DIFFERENTIATE IN VITRO AND/OR IN VIVO INTO CELLS OF DIFFERENT TISSUES, SUCH AS NEUROECTODERMAL CELL TYPES. RECENTLY, PROTOCOLS FOR HIGH-YIELD GENERATION OF UNDIFFERENTIATED NEURAL STEM CELL (NSC)-LIKE CELLS FROM MSCS OF PRIMATE AND HUMAN ORIGIN WERE REPORTED. UNDIFFERENTIATED NSCS ARE COMMONLY USED AND ARE MORE SUITABLE FOR NEUROTRANSPLANTATION COMPARED WITH FULLY DIFFERENTIATED NEURAL CELLS, AS DIFFERENTIATED NEURAL CELLS ARE WELL KNOWN TO POORLY SURVIVE DETACHMENT AND SUBSEQUENT TRANSPLANTATION PROCEDURES. THESE HUMAN MSC-DERIVED NSC-LIKE CELLS (MSC-NSCS) GROW IN NEUROSPHERE-LIKE STRUCTURES AND EXPRESS HIGH LEVELS OF EARLY NEUROECTODERMAL MARKERS, BUT LOSE CHARACTERISTICS OF MSCS. IN THE PRESENCE OF SELECTED GROWTH FACTORS, HUMAN MSC-NSCS CAN BE DIFFERENTIATED INTO THE THREE MAIN NEURAL PHENOTYPES: ASTROGLIA, OLIGODENDROGLIA AND NEURONS. COMPARED WITH DIRECT DIFFERENTIATION OF HUMAN MSCS INTO MATURE NEURAL CELLS, THE CONVERSION STEP SEEMS TO BE ESSENTIAL TO GENERATE MATURE FUNCTIONAL NEUROECTODERMAL CELLS. THIS REVIEW DESCRIBES THE TECHNIQUES FOR THE CONVERSION OF HUMAN MSCS INTO NSCS AND SUMMARISES THE DATA ON EPIGENETIC CONVERSION OF HUMAN MSCS INTO IMMATURE NEUROECTODERMAL CELLS. THESE CELLS PROVIDE A POWERFUL TOOL FOR INVESTIGATING THE MOLECULAR MECHANISMS OF NEURAL DIFFERENTIATION, AND MIGHT SERVE AS AN AUTOLOGOUS CELL SOURCE TO TREAT ACUTE AND CHRONIC NEURODEGENERATIVE DISEASES.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  1116 31 COMPARATIVE ANALYSIS OF NEUROECTODERMAL DIFFERENTIATION CAPACITY OF HUMAN BONE MARROW STROMAL CELLS USING VARIOUS CONVERSION PROTOCOLS. HUMAN ADULT BONE MARROW-DERIVED MESODERMAL STROMAL CELLS (HMSCS) ARE ABLE TO DIFFERENTIATE INTO MULTIPLE MESODERMAL TISSUES, INCLUDING BONE AND CARTILAGE. THERE IS EVIDENCE THAT THESE CELLS ARE ABLE TO BREAK GERM LAYER COMMITMENT AND DIFFERENTIATE INTO CELLS EXPRESSING NEUROECTODERMAL PROPERTIES. THERE IS STILL DEBATE ABOUT WHETHER THIS RESULTS FROM CELL FUSION, ABERRANT MARKER GENE EXPRESSION OR REAL NEUROECTODERMAL DIFFERENTIATION. HERE WE EXTEND OUR WORK ON NEUROECTODERMAL CONVERSION OF ADULT HMSCS IN VITRO BY EVALUATING VARIOUS EPIGENETIC CONVERSION PROTOCOLS USING QUANTITATIVE RT-PCR AND IMMUNOCYTOCHEMISTRY. UNDIFFERENTIATED HMSCS EXPRESSED HIGH LEVELS OF FIBRONECTIN AS WELL AS SEVERAL NEUROECTODERMAL GENES COMMONLY USED TO CHARACTERIZE NEURAL CELL TYPES, SUCH AS NESTIN, BETA-TUBULIN III, AND GFAP, SUGGESTING THAT HMSCS RETAIN THE ABILITY TO DIFFERENTIATE INTO NEUROECTODERMAL CELL TYPES. PROTOCOLS USING A DIRECT DIFFERENTIATION OF HMSCS INTO A NEURAL PHENOTYPE FAILED TO INDUCE SIGNIFICANT CHANGES IN MORPHOLOGY AND/OR EXPRESSION OF MARKERS OF EARLY AND MATURE GLIAL/NEURONAL CELLS TYPES. IN CONTRAST, A MULTISTEP PROTOCOL WITH CONVERSION OF HMSCS INTO A NEURAL STEM CELL-LIKE POPULATION AND SUBSEQUENT TERMINAL DIFFERENTIATION IN MATURE GLIA AND NEURONS GENERATED RELEVANT MORPHOLOGICAL CHANGES AS WELL AS SIGNIFICANT INCREASE OF EXPRESSION LEVELS OF MARKER GENES FOR EARLY AND LATE NEURAL CELL TYPES, SUCH AS NESTIN, NEUROGENIN2, MBP, AND MAP2AB, ACCOMPANIED BY A LOSS OF THEIR MESENCHYMAL PROPERTIES. OUR DATA PROVIDE AN IMPETUS FOR DIFFERENTIATING HMSCS IN VITRO INTO MATURE NEUROECTODERMAL CELLS. NEUROECTODERMALLY CONVERTED HMSCS MAY THEREFORE ULTIMATELY HELP IN TREATING ACUTE AND CHRONIC NEURODEGENERATIVE DISEASES. ANALYSIS OF MARKER GENE EXPRESSION FOR CHARACTERIZATION OF NEURAL CELLS DERIVED FROM MSCS HAS TO TAKE INTO ACCOUNT THAT SEVERAL EARLY AND LATE NEUROECTODERMAL GENES ARE ALREADY EXPRESSED IN UNDIFFERENTIATED MSCS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  4691 30 NEWBORNS OF OBESE PARENTS HAVE ALTERED DNA METHYLATION PATTERNS AT IMPRINTED GENES. BACKGROUND: SEVERAL EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED ASSOCIATIONS BETWEEN PERICONCEPTIONAL ENVIRONMENTAL EXPOSURES AND HEALTH STATUS OF THE OFFSPRING IN LATER LIFE. ALTHOUGH THESE ENVIRONMENTALLY RELATED EFFECTS HAVE BEEN ATTRIBUTED TO EPIGENETIC CHANGES, SUCH AS DNA METHYLATION SHIFTS AT IMPRINTED GENES, LITTLE IS KNOWN ABOUT THE POTENTIAL EFFECTS OF MATERNAL AND PATERNAL PRECONCEPTIONAL OVERNUTRITION OR OBESITY. OBJECTIVE: WE EXAMINED PARENTAL PRECONCEPTIONAL OBESITY IN RELATION TO DNA METHYLATION PROFILES AT MULTIPLE HUMAN IMPRINTED GENES IMPORTANT IN NORMAL GROWTH AND DEVELOPMENT, SUCH AS: MATERNALLY EXPRESSED GENE 3 (MEG3), MESODERM-SPECIFIC TRANSCRIPT (MEST), PATERNALLY EXPRESSED GENE 3 (PEG3), PLEIOMORPHIC ADENOMA GENE-LIKE 1 (PLAGL1), EPSILON SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 (SGCE/PEG10) AND NEURONATIN (NNAT). METHODS: WE MEASURED METHYLATION PERCENTAGES AT THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) BY BISULFITE PYROSEQUENCING IN DNA EXTRACTED FROM UMBILICAL CORD BLOOD LEUKOCYTES OF 92 NEWBORNS. PRECONCEPTIONAL OBESITY, DEFINED AS BMI ?30 KG M(-2), WAS ASCERTAINED THROUGH STANDARDIZED QUESTIONNAIRES. RESULTS: AFTER ADJUSTING FOR POTENTIAL CONFOUNDERS AND CLUSTER EFFECTS, PATERNAL OBESITY WAS SIGNIFICANTLY ASSOCIATED WITH LOWER METHYLATION LEVELS AT THE MEST (BETA=-2.57; S.E.=0.95; P=0.008), PEG3 (BETA=-1.71; S.E.=0.61; P=0.005) AND NNAT (BETA=-3.59; S.E.=1.76; P=0.04) DMRS. CHANGES RELATED TO MATERNAL OBESITY DETECTED AT OTHER LOCI WERE AS FOLLOWS: BETA-COEFFICIENT WAS +2.58 (S.E.=1.00; P=0.01) AT THE PLAGL1 DMR AND -3.42 (S.E.=1.69; P=0.04) AT THE MEG3 DMR. CONCLUSION: WE FOUND ALTERED METHYLATION OUTCOMES AT MULTIPLE IMPRINT REGULATORY REGIONS IN CHILDREN BORN TO OBESE PARENTS, COMPARED WITH CHILDREN BORN TO NON-OBESE PARENTS. IN SPITE OF THE SMALL SAMPLE SIZE, OUR DATA SUGGEST A PRECONCEPTIONAL INFLUENCE OF PARENTAL LIFE-STYLE OR OVERNUTRITION ON THE (RE)PROGRAMMING OF IMPRINT MARKS DURING GAMETOGENESIS AND EARLY DEVELOPMENT. MORE SPECIFICALLY, THE SIGNIFICANT AND INDEPENDENT ASSOCIATION BETWEEN PATERNAL OBESITY AND THE OFFSPRING'S METHYLATION STATUS SUGGESTS THE SUSCEPTIBILITY OF THE DEVELOPING SPERM FOR ENVIRONMENTAL INSULTS. THE ACQUIRED IMPRINT INSTABILITY MAY BE CARRIED ONTO THE NEXT GENERATION AND INCREASE THE RISK FOR CHRONIC DISEASES IN ADULTHOOD.	2015	
                                                                                                                                                                                                                                                             
5  4010 25 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  3835 27 IONISING RADIATION INDUCES PROMOTER DNA HYPOMETHYLATION AND PERTURBS TRANSCRIPTIONAL ACTIVITY OF GENES INVOLVED IN MORPHOGENESIS DURING GASTRULATION IN ZEBRAFISH. EMBRYONIC DEVELOPMENT IS PARTICULARLY VULNERABLE TO STRESS AND DNA DAMAGE, AS MUTATIONS CAN ACCUMULATE THROUGH CELL PROLIFERATION IN A WIDE NUMBER OF CELLS AND ORGANS. HOWEVER, THE BIOLOGICAL EFFECTS OF CHRONIC EXPOSURE TO IONISING RADIATION (IR) AT LOW AND MODERATE DOSE RATES (< 6 MGY/H) REMAIN LARGELY CONTROVERSIAL, RAISING CONCERNS FOR ENVIRONMENTAL PROTECTION. THE PRESENT STUDY FOCUSES ON THE MOLECULAR EFFECTS OF IR (0.005 TO 50 MGY/H) ON ZEBRAFISH EMBRYOS AT THE GASTRULA STAGE (6 HPF), AT BOTH THE TRANSCRIPTOMICS AND EPIGENETICS LEVELS. OUR RESULTS SHOW THAT EXPOSURE TO IR MODIFIES THE EXPRESSION OF GENES INVOLVED IN MITOCHONDRIAL ACTIVITY FROM 0.5 TO 50 MGY/H. IN ADDITION, IMPORTANT DEVELOPMENTAL PATHWAYS, NAMELY, THE NOTCH, RETINOIC ACID, BMP AND WNT SIGNALLING PATHWAYS, WERE ALTERED AT 5 AND 50 MGY/H. TRANSCRIPTIONAL CHANGES OF GENES INVOLVED IN THE MORPHOGENESIS OF THE ECTODERM AND MESODERM WERE DETECTED AT ALL DOSE RATES, BUT WERE PROMINENT FROM 0.5 TO 50 MGY/H. AT THE EPIGENETIC LEVEL, EXPOSURE TO IR INDUCED A HYPOMETHYLATION OF DNA IN THE PROMOTER OF GENES THAT COLOCALISED WITH BOTH H3K27ME3 AND H3KME4 HISTONE MARKS AND CORRELATED WITH CHANGES IN TRANSCRIPTIONAL ACTIVITY. FINALLY, PATHWAY ENRICHMENT ANALYSIS DEMONSTRATED THAT THE DNA METHYLATION CHANGES OCCURRED IN THE PROMOTER OF IMPORTANT DEVELOPMENTAL GENES, INCLUDING MORPHOGENESIS OF THE ECTODERM AND MESODERM. TOGETHER, THESE RESULTS SHOW THAT THE TRANSCRIPTIONAL PROGRAM REGULATING MORPHOGENESIS IN GASTRULATING EMBRYOS WAS MODIFIED AT DOSE RATES GREATER THAN OR EQUAL TO 0.5 MGY/H, WHICH MIGHT PREDICT POTENTIAL NEUROGENESIS AND SOMITOGENESIS DEFECTS OBSERVED AT SIMILAR DOSE RATES LATER IN DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  6757 39 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8    80 27 A NEW ROLE FOR THE P2Y-LIKE GPR17 RECEPTOR IN THE MODULATION OF MULTIPOTENCY OF OLIGODENDROCYTE PRECURSOR CELLS IN VITRO. OLIGODENDROCYTE PRECURSOR CELLS (OPCS, ALSO CALLED NG2 CELLS) ARE SCATTERED THROUGHOUT BRAIN PARENCHYMA, WHERE THEY FUNCTION AS A RESERVOIR TO REPLACE LOST OR DAMAGED OLIGODENDROCYTES, THE MYELIN-FORMING CELLS. THE HYPOTHESIS THAT, UNDER SOME CIRCUMSTANCES, OPCS CAN ACTUALLY BEHAVE AS MULTIPOTENT CELLS, THUS GENERATING ASTROCYTES AND NEURONS AS WELL, HAS ARISEN FROM SOME IN VITRO AND IN VIVO EVIDENCE, BUT THE MOLECULAR PATHWAYS CONTROLLING THIS ALTERNATIVE FATE OF OPCS ARE NOT FULLY UNDERSTOOD. THEIR IDENTIFICATION WOULD OPEN NEW OPPORTUNITIES FOR NEURONAL REPLACE STRATEGIES, BY FOSTERING THE INTRINSIC ABILITY OF THE BRAIN TO REGENERATE. HERE, WE SHOW THAT THE ANTI-EPILEPTIC EPIGENETIC MODULATOR VALPROIC ACID (VPA) CAN PROMOTE THE GENERATION OF NEW NEURONS FROM NG2(+) OPCS UNDER NEUROGENIC PROTOCOLS IN VITRO, THROUGH THEIR INITIAL DE-DIFFERENTIATION TO A STEM CELL-LIKE PHENOTYPE THAT THEN EVOLVES TO "HYBRID" CELL POPULATION, SHOWING OPC MORPHOLOGY BUT EXPRESSING THE NEURONAL MARKER BETAIII-TUBULIN AND THE GPR17 RECEPTOR, A KEY DETERMINANT IN DRIVING OPC TRANSITION TOWARDS MYELINATING OLIGODENDROCYTES. UNDER THESE CONDITIONS, THE PHARMACOLOGICAL BLOCKADE OF THE P2Y-LIKE RECEPTOR GPR17 BY CANGRELOR, A DRUG RECENTLY APPROVED FOR HUMAN USE, PARTIALLY MIMICS THE EFFECTS MEDIATED BY VPA THUS ACCELERATING CELLS' NEUROGENIC CONVERSION. THESE DATA SHOW A CO-LOCALIZATION BETWEEN NEURONAL MARKERS AND GPR17 IN VITRO, AND SUGGEST THAT, BESIDES ITS INVOLVEMENT IN OLIGODENDROGENESIS, GPR17 CAN DRIVE THE FATE OF NEURAL PRECURSOR CELLS BY INSTRUCTING PRECURSORS TOWARDS THE NEURONAL LINEAGE. BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL "DRUGGABLE" TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC BRAIN DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9   520 24 ASSOCIATIONS BETWEEN MATERNAL PRENATAL STRESS, METHYLATION CHANGES IN IGF1 AND IGF2, AND BIRTH WEIGHT. MATERNAL STRESS HAS BEEN LINKED TO LOW BIRTH WEIGHT IN NEWBORNS. ONE POTENTIAL PATHWAY INVOLVES EPIGENETIC CHANGES AT CANDIDATE GENES THAT MAY MEDIATE THE EFFECTS OF PRENATAL MATERNAL STRESS ON BIRTH WEIGHT. THIS RELATIONSHIP HAS BEEN DOCUMENTED IN STRESS-RELATED GENES, SUCH AS NR3C1. THERE IS LESS LITERATURE EXPLORING THE EFFECT OF STRESS ON GROWTH-RELATED GENES. IGF1 AND IGF2 HAVE BEEN IMPLICATED IN FETAL GROWTH AND DEVELOPMENT, THOUGH VIA DIFFERENT MECHANISMS AS IGF2 IS UNDER IMPRINTING CONTROL. IN THIS STUDY, WE TESTED FOR ASSOCIATIONS BETWEEN PRENATAL STRESS, METHYLATION OF IGF1 AND IGF2, AND BIRTH WEIGHT. A TOTAL OF 24 MOTHER-NEWBORN DYADS IN THE DEMOCRATIC REPUBLIC OF CONGO WERE ENROLLED. ETHNOGRAPHIC INTERVIEWS WERE CONDUCTED WITH MOTHERS AT DELIVERY TO GATHER CULTURALLY RELEVANT WAR-RELATED AND CHRONIC STRESSORS. DNA METHYLATION DATA WERE GENERATED FROM MATERNAL VENOUS, CORD BLOOD AND PLACENTAL TISSUE SAMPLES. MULTIVARIATE REGRESSIONS WERE USED TO TEST FOR ASSOCIATIONS BETWEEN STRESS MEASURES, DNA METHYLATION AND BIRTH WEIGHT IN EACH OF THE THREE TISSUE TYPES. WE FOUND AN ASSOCIATION BETWEEN IGF2 METHYLATION IN MATERNAL BLOOD AND BIRTH WEIGHT. PREVIOUS LITERATURE ON THE RELATIONSHIP BETWEEN IGF2 METHYLATION AND BIRTH WEIGHT HAS FOCUSED ON METHYLATION AT KNOWN DIFFERENTIALLY METHYLATED REGIONS IN CORD BLOOD OR PLACENTAL SAMPLES. OUR FINDINGS INDICATE THERE MAY BE LINKS BETWEEN THE MATERNAL EPIGENOME AND LOW BIRTH WEIGHT THAT RELY ON MECHANISMS OUTSIDE KNOWN IMPRINTING PATHWAYS. IT THUS MAY BE IMPORTANT TO CONSIDER THE EFFECT OF MATERNAL EXPOSURES AND EPIGENETIC PROFILES ON BIRTH WEIGHT EVEN IN THE SETTING OF MATERNALLY IMPRINTED GENES SUCH AS IGF2.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  5661 25 SEXUAL DIMORPHISM IN EPIGENOMIC RESPONSES OF STEM CELLS TO EXTREME FETAL GROWTH. EXTREME FETAL GROWTH IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO A RANGE OF ADULT DISEASES THROUGH AN UNKNOWN MECHANISM OF CELLULAR MEMORY. WE TESTED WHETHER HERITABLE EPIGENETIC PROCESSES IN LONG-LIVED CD34(+) HAEMATOPOIETIC STEM/PROGENITOR CELLS SHOWED EVIDENCE FOR RE-PROGRAMMING ASSOCIATED WITH THE EXTREMES OF FETAL GROWTH. HERE WE SHOW THAT BOTH FETAL GROWTH RESTRICTION AND OVER-GROWTH ARE ASSOCIATED WITH GLOBAL SHIFTS TOWARDS DNA HYPERMETHYLATION, TARGETING CIS-REGULATORY ELEMENTS IN PROXIMITY TO GENES INVOLVED IN GLUCOSE HOMEOSTASIS AND STEM CELL FUNCTION. WE FIND A SEXUALLY DIMORPHIC RESPONSE; INTRAUTERINE GROWTH RESTRICTION IS ASSOCIATED WITH SUBSTANTIALLY GREATER EPIGENETIC DYSREGULATION IN MALES, WHEREAS LARGE FOR GESTATIONAL AGE GROWTH PREDOMINANTLY AFFECTS FEMALES. THE FINDINGS ARE CONSISTENT WITH EXTREME FETAL GROWTH INTERACTING WITH VARIABLE FETAL SUSCEPTIBILITY TO INFLUENCE CELLULAR AGEING AND METABOLIC CHARACTERISTICS THROUGH EPIGENETIC MECHANISMS, POTENTIALLY GENERATING BIOMARKERS THAT COULD IDENTIFY INFANTS AT HIGHER RISK FOR CHRONIC DISEASE LATER IN LIFE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11     4 26 "MIX OF MICS"- PHENOTYPIC AND BIOLOGICAL HETEROGENEITY OF "MULTIPOTENT" MUSCLE INTERSTITIAL CELLS (MICS). THE CAPACITY OF ADULT SKELETAL MUSCLE FOR REGENERATION APPEARS TO BE LIMITED, WITH PROGRESSIVE IMPAIRMENT IN REPAIR EFFICIENCY OF INJURED MUSCLES OBSERVED IN CHRONIC MUSCULAR DISORDERS AND DURING AGING. WHILE SATELLITE CELLS, THE COMMITTED ADULT MUSCLE STEM CELLS, ARE THE MAIN DIRECT CELL SOURCE SUPPORTING THE REGENERATIVE POTENTIAL OF ADULT SKELETAL MUSCLES, THE CHARACTERIZATION OF THE CELL TYPES AND SIGNALS THAT CONSTITUTE THE FUNCTIONAL "NICHE" OF SATELLITE CELLS IS CURRENTLY THE OBJECT OF INTENSE INVESTIGATION. RECENT STUDIES HAVE IDENTIFIED A FUNCTIONAL RELATIONSHIP BETWEEN SATELLITE CELLS AND VARIOUS CELL TYPES LOCATED IN KEY ANATOMICAL POSITION, SUCH AS THE INTERSTITIUM OF SKELETAL MUSCLES. THIS HETEROGENEOUS POPULATION OF MUSCLE INTERSTITIAL CELLS (MICS) APPEARS TO RETAIN AN INTRINSIC MULTIPOTENCY WITHIN THE MESODERMAL LINEAGE, AND THEIR DIRECT OR INDIRECT CONTRIBUTION TO MYOFIBER TURNOVER, REPAIR AND DEGENERATION HAS BEEN SUGGESTED BY MANY STUDIES THAT WILL BE REVIEWED HERE. GIVEN THE EXISTING GAP OF KNOWLEDGE ON LINEAGE IDENTITY AND FUNCTIONAL PROPERTIES OF MICS, THEIR DETAILED CHARACTERIZATION AT THE SINGLE CELL LEVEL HOLDS THE PROMISE TO PROVIDE KEY INSIGHT INTO THE COMPOSITION OF THIS HETEROGENEOUS POPULATION AND THE DYNAMIC TRANSITION THROUGH DISTINCT SUB-POPULATIONS IN HEALTHY, DISEASED AND AGING MUSCLES. THIS REVIEW PROVIDES AN OVERVIEW OF THE RESULTS OF VARIOUS STUDIES DESCRIBING THE PHENOTYPE AND THE FUNCTION OF CELLS ISOLATED FROM SKELETAL MUSCLE INTERSTITIUM, AND DISCUSSES THE IMPORTANCE OF SINGLE CELL TRANSCRIPTION PROFILING IN ORDER TO DECIPHER THE FUNCTIONAL AND PHENOTYPICAL HETEROGENEITY OF MUSCLE INTERSTITIAL CELLS (MICS).	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12  2468 28 EPIGENETIC TOXICOLOGY AS TOXICANT-INDUCED CHANGES IN INTRACELLULAR SIGNALLING LEADING TO ALTERED GAP JUNCTIONAL INTERCELLULAR COMMUNICATION. COMMUNICATION MECHANISMS [EXTRA-, INTRA-, AND GAP JUNCTIONAL INTER-CELLULAR COMMUNICATION (GJIC)] CONTROL, FROM THE FERTILIZED EGG, THROUGH EMBRYOGENESIS TO MATURITY AND AGING, WHETHER A CELL PROLIFERATES, DIFFERENTIATES, DIES BY APOPTOSIS, OR IF DIFFERENTIATED, ADAPTIVELY RESPONDS TO ENDOGENOUS AND EXOGENOUS SIGNALS. FROM THE EGG TO THE 100 TRILLION CELLS IN THE HUMAN BODY, HEALTH IS MAINTAINED WHEN THESE COMMUNICATION PROCESSES BETWEEN STEM, PROGENITOR AND TERMINALLY DIFFERENTIATED CELLS ARE INTEGRATED. EACH CELL CHOICE INVOLVES 'EPIGENETIC' MECHANISMS TO ALTER THE EXPRESSION OF GENES AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS. DISRUPTION OF THE COMMUNICATION MECHANISMS CAN BE EITHER ADAPTIVE OR MALADAPTIVE. MODULATION OF EXTRA-CELLULAR COMMUNICATION, EITHER BY GENETIC IMBALANCES OF GROWTH FACTORS, HORMONES OR NEUROTRANSMITTERS OR BY ENVIRONMENTAL, EXOGENOUS CHEMICALS CAN TRIGGER SIGNAL TRANSDUCING INTRA-CELLULAR MECHANISMS. THESE INTRA-CELLULAR SIGNALS CAN MODULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS WHILE ALSO MODULATING GJIC. UNTIMELY OR CHRONIC DISRUPTION OF GJIC DURING EMBRYONIC OR FETAL DEVELOPMENT COULD LEAD TO EMBRYONIC LETHALITY OR TERATOGENESIS. BY MODULATION OF GJIC, HOMEOSTATIC CONTROL OF CELL GROWTH, DIFFERENTIATION OR APOPTOSIS COULD LEAD TO SPECIFIC DISEASES, SUCH AS NEUROLOGICAL, CARDIOVASCULAR, REPRODUCTIVE OR ENDOCRINOLOGICAL DYSFUNCTION. CHEMICAL MODULATION OR ONCOGENE DOWN-REGULATION OF GJIC IN INITIATED TISSUES HAS BEEN SHOWN TO LEAD TO TUMOR PROMOTION. GENETIC SYNDROMES CARRYING A MUTATED GAP JUNCTION GENE, TOGETHER WITH SOME TRANSGENIC AND KNOCK-OUT GAP JUNCTION GENE MICE, PROVIDE EVIDENCE FOR THE IMPORTANCE OF THIS ORGANELLE FOUND ONLY IN METAZOANS. IMPLICATIONS FOR 'THRESHOLDS' TO TOXICANTS AND FOR RISK ASSESSMENT ARE EVIDENT.	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13   930 21 CHRONIC IRRADIATION OF HUMAN CELLS REDUCES HISTONE LEVELS AND DEREGULATES GENE EXPRESSION. OVER THE PAST DECADES, THERE HAVE BEEN HUGE ADVANCES IN UNDERSTANDING CELLULAR RESPONSES TO IONISING RADIATION (IR) AND DNA DAMAGE. THESE STUDIES, HOWEVER, WERE MOSTLY EXECUTED WITH CELL LINES AND MICE USING SINGLE OR MULTIPLE ACUTE DOSES OF RADIATION. HENCE, RELATIVELY LITTLE IS KNOWN ABOUT HOW CONTINUOUS EXPOSURE TO LOW DOSE IONISING RADIATION AFFECTS NORMAL CELLS AND ORGANISMS, EVEN THOUGH OUR CELLS ARE CONSTANTLY EXPOSED TO LOW LEVELS OF RADIATION. WE ADDRESSED THIS ISSUE BY EXAMINING THE CONSEQUENCES OF EXPOSING HUMAN PRIMARY CELLS TO CONTINUOUS IONISING GAMMA-RADIATION DELIVERED AT 6-20 MGY/H. ALTHOUGH THESE DOSE RATES ARE ESTIMATED TO INFLICT FEWER THAN A SINGLE DNA DOUBLE-STRAND BREAK (DSB) PER HOUR PER CELL, THEY STILL CAUSED DOSE-DEPENDENT REDUCTIONS IN CELL PROLIFERATION AND INCREASED CELLULAR SENESCENCE. WE CONCOMITANTLY OBSERVED HISTONE PROTEIN LEVELS TO REDUCE BY UP TO 40%, WHICH IN CONTRAST TO PREVIOUS OBSERVATIONS, WAS NOT MAINLY DUE TO PROTEIN DEGRADATION BUT INSTEAD CORRELATED WITH REDUCED HISTONE GENE EXPRESSION. HISTONE REDUCTIONS WERE ACCOMPANIED BY ENLARGED NUCLEAR SIZE PARALLELED BY AN INCREASE IN GLOBAL TRANSCRIPTION, INCLUDING THAT OF PRO-INFLAMMATORY GENES. THUS, CHRONIC IRRADIATION, EVEN AT LOW DOSE-RATES, CAN INDUCE CELL SENESCENCE AND ALTER GENE EXPRESSION VIA A HITHERTO UNCHARACTERISED EPIGENETIC ROUTE. THESE FEATURES OF CHRONIC RADIATION REPRESENT A NEW ASPECT OF RADIATION BIOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14  5200 21 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15   518 27 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  4223 23 METHYLATION CHANGES AT NR3C1 IN NEWBORNS ASSOCIATE WITH MATERNAL PRENATAL STRESS EXPOSURE AND NEWBORN BIRTH WEIGHT. EARLY LIFE EXPERIENCES, INCLUDING THOSE IN UTERO, HAVE BEEN LINKED TO INCREASED RISK FOR ADULT-ONSET CHRONIC DISEASE. THE UNDERLYING ASSUMPTION IS THAT THERE IS A CRITICAL PERIOD OF DEVELOPMENTAL PLASTICITY IN UTERO WHEN SELECTION OF THE FETAL PHENOTYPE THAT IS BEST ADAPTED TO THE INTRAUTERINE ENVIRONMENT OCCURS. THE CURRENT STUDY IS THE FIRST TO TEST THE IDEA THAT EXTREME MATERNAL PSYCHOSOCIAL STRESSORS, AS OBSERVED IN THE DEMOCRATIC REPUBLIC OF CONGO, MAY MODIFY LOCUS-SPECIFIC EPIGENETIC MARKS IN THE NEWBORN RESULTING IN ALTERED HEALTH OUTCOMES. HERE WE SHOW A SIGNIFICANT CORRELATION BETWEEN CULTURALLY RELEVANT MEASURES OF MATERNAL PRENATAL STRESS, NEWBORN BIRTH WEIGHT AND NEWBORN METHYLATION IN THE PROMOTER OF THE GLUCOCORTICOID RECEPTOR NR3C1. INCREASED METHYLATION MAY CONSTRAIN PLASTICITY IN SUBSEQUENT GENE EXPRESSION AND RESTRICT THE RANGE OF STRESS ADAPTATION RESPONSES POSSIBLE IN AFFECTED INDIVIDUALS, THUS INCREASING THEIR RISK FOR ADULT-ONSET DISEASES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   260 22 ADVANCES IN RESEARCH INTO GAMETE AND EMBRYO-FETAL ORIGINS OF ADULT DISEASES. THE FETAL AND INFANT ORIGINS OF ADULT DISEASE HYPOTHESIS PROPOSED THAT THE ROOTS OF ADULT CHRONIC DISEASE LIE IN THE EFFECTS OF ADVERSE ENVIRONMENTS IN FETAL LIFE AND EARLY INFANCY. IN ADDITION TO THE FETAL PERIOD, FERTILIZATION AND EARLY EMBRYONIC STAGES, THE CRITICAL TIME WINDOWS OF EPIGENETIC REPROGRAMMING, RAPID CELL DIFFERENTIATION AND ORGANOGENESIS, ARE THE MOST SENSITIVE STAGES TO ENVIRONMENTAL DISTURBANCES. COMPARED WITH EMBRYO AND FETAL DEVELOPMENT, GAMETOGENESIS AND MATURATION TAKE DECADES AND ARE MORE VULNERABLE TO POTENTIAL DAMAGE FOR A LONGER EXPOSURE PERIOD. THEREFORE, WE SHOULD SHIFT THE FOCUS OF ADULT DISEASE OCCURRENCE AND PATHOGENESIS FURTHER BACK TO GAMETOGENESIS AND EMBRYONIC DEVELOPMENT EVENTS, WHICH MAY RESULT IN INTERGENERATIONAL, EVEN TRANSGENERATIONAL, EPIGENETIC RE-PROGRAMMING WITH TRANSMISSION OF ADVERSE TRAITS AND CHARACTERISTICS TO OFFSPRING. HERE, WE FOCUS ON THE RESEARCH PROGRESS RELATING TO DISEASES THAT ORIGINATED FROM EVENTS IN THE GAMETES AND EARLY EMBRYOS AND THE POTENTIAL EPIGENETIC MECHANISMS INVOLVED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  2069 29 EPIGENETIC CONTROL OF SKELETAL MUSCLE REGENERATION: INTEGRATING GENETIC DETERMINANTS AND ENVIRONMENTAL CHANGES. DURING EMBRYONIC DEVELOPMENT, PLURIPOTENT CELLS ARE GENETICALLY COMMITTED TO SPECIFIC LINEAGES BY THE EXPRESSION OF CELL-TYPE-SPECIFIC TRANSCRIPTIONAL ACTIVATORS THAT DIRECT THE FORMATION OF SPECIALIZED TISSUES AND ORGANS IN RESPONSE TO DEVELOPMENTAL CUES. CHROMATIN-MODIFYING PROTEINS ARE EMERGING AS ESSENTIAL COMPONENTS OF THE EPIGENETIC MACHINERY, WHICH ESTABLISHES THE NUCLEAR LANDSCAPE THAT ULTIMATELY DETERMINES THE FINAL IDENTITY AND FUNCTIONAL SPECIALIZATION OF ADULT CELLS. RECENT EVIDENCE HAS REVEALED THAT DISCRETE POPULATIONS OF ADULT CELLS CAN RETAIN THE ABILITY TO ADOPT ALTERNATIVE CELL FATES IN RESPONSE TO ENVIRONMENTAL CUES. THESE CELLS INCLUDE CONVENTIONAL ADULT STEM CELLS AND A STILL POORLY DEFINED COLLECTION OF CELL TYPES ENDOWED WITH FACULTATIVE PHENOTYPE AND FUNCTIONAL PLASTICITY. UNDER PHYSIOLOGICAL CONDITIONS OR ADAPTIVE STATES, THESE CELLS COOPERATE TO SUPPORT TISSUE AND ORGAN HOMEOSTASIS, AND TO PROMOTE GROWTH OR COMPENSATORY REGENERATION. HOWEVER, DURING CHRONIC DISEASES AND AGING THESE CELLS CAN ADOPT A PATHOLOGICAL PHENOTYPE AND MEDIATE MALADAPTIVE RESPONSES, SUCH AS THE FORMATION OF FIBROTIC SCARS AND FAT DEPOSITION THAT PROGRESSIVELY REPLACES STRUCTURAL AND FUNCTIONAL UNITS OF TISSUES AND ORGANS. THE MOLECULAR DETERMINANTS OF THESE PHENOTYPIC TRANSITIONS ARE ONLY EMERGING FROM RECENT STUDIES THAT REVEAL HOW DYNAMIC CHROMATIN STATES CAN GENERATE FLEXIBLE EPIGENETIC LANDSCAPES, WHICH CONFER ON CELLS THE ABILITY TO RETAIN PARTIAL PLURIPOTENCY AND ADAPT TO ENVIRONMENTAL CHANGES. THIS REVIEW SUMMARIZES OUR CURRENT KNOWLEDGE ON THE ROLE OF THE EPIGENETIC MACHINERY AS A 'FILTER' BETWEEN GENETIC COMMITMENT AND ENVIRONMENTAL SIGNALS IN CELL TYPES THAT CAN ALTERNATIVELY PROMOTE SKELETAL MUSCLE REGENERATION OR FIBRO-ADIPOGENIC DEGENERATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  2772 28 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES.	2003	

20   621 25 BIOENERGETIC EVOLUTION EXPLAINS PREVALENCE OF LOW NEPHRON NUMBER AT BIRTH: RISK FACTOR FOR CKD. THERE IS GREATER THAN TENFOLD VARIATION IN NEPHRON NUMBER OF THE HUMAN KIDNEY AT BIRTH. ALTHOUGH LOW NEPHRON NUMBER IS A RECOGNIZED RISK FACTOR FOR CKD, ITS DETERMINANTS ARE POORLY UNDERSTOOD. EVOLUTIONARY MEDICINE REPRESENTS A NEW DISCIPLINE THAT SEEKS EVOLUTIONARY EXPLANATIONS FOR DISEASE, BROADENING PERSPECTIVES ON RESEARCH AND PUBLIC HEALTH INITIATIVES. EVOLUTION OF THE KIDNEY, AN ORGAN RICH IN MITOCHONDRIA, HAS BEEN DRIVEN BY NATURAL SELECTION FOR REPRODUCTIVE FITNESS CONSTRAINED BY ENERGY AVAILABILITY. OVER THE PAST 2 MILLION YEARS, RAPID GROWTH OF AN ENERGY-DEMANDING BRAIN IN HOMO SAPIENS ENABLED HOMINID ADAPTATION TO ENVIRONMENTAL EXTREMES THROUGH SELECTION FOR MUTATIONS IN MITOCHONDRIAL AND NUCLEAR DNA EPIGENETICALLY REGULATED BY ALLOCATION OF ENERGY TO DEVELOPING ORGANS. MATERNAL UNDERNUTRITION OR HYPOXIA RESULTS IN INTRAUTERINE GROWTH RESTRICTION OR PRETERM BIRTH, RESULTING IN LOW BIRTH WEIGHT AND LOW NEPHRON NUMBER. REGULATED THROUGH PLACENTAL TRANSFER, ENVIRONMENTAL OXYGEN AND NUTRIENTS SIGNAL NEPHRON PROGENITOR CELLS TO REPROGRAM METABOLISM FROM GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION. THESE PROCESSES ARE MODULATED BY COUNTERBALANCING ANABOLIC AND CATABOLIC METABOLIC PATHWAYS THAT EVOLVED FROM PROKARYOTE HOMOLOGS AND BY HYPOXIA-DRIVEN AND AUTOPHAGY PATHWAYS THAT EVOLVED IN EUKARYOTES. REGULATION OF NEPHRON DIFFERENTIATION BY HISTONE MODIFICATIONS AND DNA METHYLTRANSFERASES PROVIDE EPIGENETIC CONTROL OF NEPHRON NUMBER IN RESPONSE TO ENERGY AVAILABLE TO THE FETUS. DEVELOPMENTAL PLASTICITY OF NEPHROGENESIS REPRESENTS AN EVOLVED LIFE HISTORY STRATEGY THAT PRIORITIZES ENERGY TO EARLY BRAIN GROWTH WITH ADEQUATE KIDNEY FUNCTION THROUGH REPRODUCTIVE YEARS, THE TRADE-OFF BEING INCREASING PREVALENCE OF CKD DELAYED UNTIL LATER ADULTHOOD. THE RESEARCH IMPLICATIONS OF THIS EVOLUTIONARY ANALYSIS ARE TO IDENTIFY REGULATORY PATHWAYS OF ENERGY ALLOCATION DIRECTING NEPHROGENESIS WHILE ACCOUNTING FOR THE DIFFERENT LIFE HISTORY STRATEGIES OF ANIMAL MODELS SUCH AS THE MOUSE. THE CLINICAL IMPLICATIONS ARE TO OPTIMIZE NUTRITION AND MINIMIZE HYPOXIC/TOXIC STRESSORS IN CHILDBEARING WOMEN AND CHILDREN IN EARLY POSTNATAL DEVELOPMENT.	2020